Mechanisms of Telomere Length Maintenance by Telomerase and Its Role in the Evasion of Senescence by Cancer Cells

Telomeres, the repetitive nucleoprotein structures capping eukaryotic chromosome ends, progressively shorten with each cell division due to the end-replication problem, ultimately triggering replicative senescence through ATM/ATR-mediated activation of the p۵۳/p۲۱ and p۱۶/RB pathways. In normal somatic cells, this mechanism acts as an intrinsic tumor-suppressive barrier that limits unchecked proliferation. Telomerase, a specialized ribonucleoprotein enzyme composed of the catalytic subunit TERT and the RNA template TERC, counteracts this shortening by processively extending the chromosomal ۳′ overhang, with recruitment and efficiency further regulated by the shelterin complex, particularly TPP۱. In the majority of human cancers, recurrent TERT promoter mutations reactivate this otherwise silenced enzyme, allowing malignant cells to bypass senescence and apoptosis, cross the genomic crisis checkpoint, and achieve replicative immortality—one of the defining hallmarks of cancer. This review summarizes the structural basis of telomere maintenance, the molecular mechanism of telomerase-mediated repeat addition, and the multiple layers through which telomerase reactivation enables cancer cells to escape cellular aging. The clinical relevance of telomerase as a near-universal, selective therapeutic target is also discussed, including FDA-approved and emerging telomerase-targeted strategies, alongside the persistent challenges of treatment latency and ALT-mediated resistance that continue to limit broader clinical success

کلیدواژه ها:

telomerase ، telomere shortening ، cellular senescence ، replicative immortality ، cancer hallmarks ، TERT promoter mutation ، telomerase inhibitors